Preparation of symmetrical 4-(dialkylamino)phenols

ABSTRACT

1. A PROCESS FOR PREPARING SYMMETRICAL 4-(DIALKYLAMINO)PHENOLS CORRESPONDING TO THE FORMULA   4-((R)2-N-),(X)N-PHENOL   WHEREIN R REPRESENTS LOWERALKYL OF 1 TO 4 CARBON ATOMS OR BOTH R GROUPS TAKEN TOGETHER WITH THE NITROGEN ATOM REPRESENT PIPERIDINO, MORPHOLINO OR PYRROLIDINO; X REPRESENTS LOWERALKYL OF 1 TO 4 CARBON ATOMS OR LOWERALKOXY OF 1 TO 4 CARBON ATOMS AND N REPRESENTS AN INTEGER OF 0 TO 3 WITH THE PROVISO THAT WHEN X IS TERITARY BUTYL OR TERTIARY BUTOXY, THAT ONLY ONE SUCH MOIETY CAN BE IN A RING POSITION ALPHA TO THE AMINO NITROGEN, WHICH CONSISTS ESSENTIALLY OF REACTING IN AN INERT POLAR SOLVENT, A 4-BROMOPHENOL OF THE FORMULA WHEREIN X AND N ARE AS SET FORTH HEREINBEFORE, WITH A COMPOUND OF THE FORMULA   HN(R)2   WHEREIN R IS AS SET FORTH HEREINBEFORE, AT A PRESSURE ABOVE ATMOSPHERIC PRESSURE AND AT A TEMPERATURE OF FROM ABOUT 100*C. TO ABOUT 300*C.

United States Patent Oificc 3,845,063 Patented Oct. 29, 1974 3,845,063PREPARATION OF SYMMETRICAL 4-(DIALKYLAMINO)PHENOLS Dean M. Balls,Chamblee, Ga., assignor to The Dow Chemical Company, Midland, Mich. NoDrawing. Continuation-impart of application Ser. No. 102,179, Dec. 28,1970, which is a continuation-in-part of application Ser. No. 60,646,Aug. 3, 1970, both now abandoned. This application Dec. 29, 1972, Ser.No.

Int. Cl. C07d 29/16 US. Cl. 260--293.84 13 Claims ABSTRACT OF THEDISCLOSURE Symmetrical 4-(dialkylamino)phenols are prepared by a methodwhich comprises reacting in the presence of an inert polar solvent a4-bromophenol with a saturated compound having an amino type nitrogenatom which has one replaceable hydrogen atom thereon.

CROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of my copending application, Ser. No. 102,179,filed Dec. 28, .1970, now abandoned which in turn is acontinuation-in-part of my application Ser. No. 60,646, filed Aug. 3,1970, now abandoned.

BACKGROUND OF THE INVENTION The invention relates to an improved processfor preparing symmetrical 4(dialkylamino)phenols corresponding to thegeneral formula (I) In this and succeeding formulae, R representslowerallryl of 1 to 4 carbon atoms, or both R groups taken together withthe nitrogen atom represented piperidino, morpholino or pyrrolidino; Xrepresents loweralkyl of 1 to 4 carbon atoms or loweralkoxy of 1 to 4carbon atoms and n represents an integer of to 3 with the proviso thatwhen X is tertiary butyl or tertiary butoxy, that only one such moietycan be in a ring position alpha to the amino nitrogen.

Representative loweralkyl radicals include, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl as wellas cyclopropyl and cyclocally substituted (dialkylamino)phenols areprepared by alkylating an appropriate 4-aminophenol with an alkylatingagent such as an alkyl sulfate in the presence of sodium bicarbonate at25 to 100 C. Another method is taught in US. Pat. 2,776,313 wherein(dialkylamino) phenols are prepared by reacting anN-monoal'kyl-paminophenol with an aliphatic aldehyde in the presence ofhydrogen and a hydrogenation catalyst at temperatures of 25 to 150 C.and hydrogen pressures of 500 to 5000 p.s.i.

While the above-described and other processes are effective, they arenot entirely satisfactory and new and improved processes are continuallybeing sought.

More particularly, these processes of the prior art are complicated bytheir cost and/ or low yields and in some, by the need to employ morethan one reaction step, and long reaction times.

SUMMARY OF THE INVENTION It has now been found that symmetrical4-(dialkylamino)phenols of formula I can be produced in desirably highyields and in a new and more economic process, by reacting in water orother inert polar solvent a 4-bromophenol corresponding to the formula lBr (II) wherein X and n are as set forth hereinbefore, with an aminetype compound corresponding to the formula HN(R) (III) wherein R is asset forth hereinbefore.

Representative compounds embraced by formula I and which can be preparedby the process disclosed and claimed herein, include, for example,

4-(diethylamino)phenol, 4-(diethylamino)-2,3,5-trimethoxyphenol.4-(di-n-propylamino)-3,5-dipropylphenol,4-(dicyclopropylamino)-2,3,5-trimethylphenol,4-(diisopropylamino)phenol, 4-(dicyclobutylamino)phenol,

4-dimethylamino)-2,6-dicyclobutoxyphenol,

butyl. Representative loweralkoxy radicals include, for

example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondarybutoxy and tertiary butoxy as well as cyclopropoxy and cyclobutoxy.

Compounds of the above formula are important materials in the field ofcommerce and their areas of activity are diverse. Some have utility inthe area of photography as developing agents as set forth in BritishPat. 928,671, US. Pat. 3,300,305 and Japanese Pat. 7,221,757. Many ofthe compounds are useful as gasoline antioxidants,

rubber antioxidants, dye intermediates and germicides as taught in US.Pat. 2,375,311, Many are useful as gum inhibitors for gasoline as taughtin US. Pat. 2,250,501 and 2,776,313. Others are useful in preparingpesticidally active sulfamates as taughtin US. Pat. 3,082,238 and manyare useful in preparing urethans having. pharmacological activity astaught by Gardner, et al., I.A.C.S., 69, 3086-8 (1947). v e

These compounds have heretofore been prepared by a number of diverse andexpensive processes such as the method taught in US. Pat. 3,060,225,wherein symmetrii ere .The desirableresults ,of thepresent. inventionare obtained by reacting the 4-brornophenol reactant and the aminereactant in water or other inert polar solvent.

While it is preferred to employ water as the reaction medium, otherinert polar solvents or mixtures of these solvents can optionally'beemployed.

Suitable inert polar solvents in addition to water which can be employedinclude methanol, ethanol, dioxane, dimethylformamide,dimethylsulfoxide, acetonitrile or aqueous solutions of any of thesesolvents.

It has been found to be practicable to employ molar ratios of the aminereactant to the phenol reactant of from about 1 to 1 to about to 1.Although it is possible to use amounts beyond this, a decrease in theamount of the amine reactant below the indicated minimum results in adecrease in the yield. The weight ratio of the amine reactant to theamount of solvent is from about 1 to 10 up to about 10 to 1. I

Representative phenol reactants include, for example,

4-bromophenol,

4-bromo-2-methylphenol; 4-bromo-3-methylphenol, 4-brorno-3-ethylphenol,4-bromo-3-isopropylphenol, 1 4-bromo-3,5-dimethylphenol,4-bromo-3,5-diethylphenol, 4-bromo-3,S-dipropylphenol,4-bromo-3-methoxyphenol, 4-bromo-2,3,5-trimethylphenol,4-bromo-2,6-di-cyclobutoxyphenol, 4-bromo-3,5-di-tertiarybutylphenol,4-bromo-2,6-di-tertiarybutylphenol, 4-bromo-3,S-dimethoxyphenol,4-bromo-2,3,S-trimethoxyphenol, 4-bromo-3-butoxyphenol,4-bromo-3,S-di-n-butylphenol, 4-bromo-2,6-di-cyclobutylphenol and4-bromo-2-ethoxyphenol.

Representative amine reactants include, for example, dimethylamine,diethylamine, di-n-propylamine, di-isopropylamine, dicyclopropylamine,di-sec-butylamine, di-tbutylamine, dicyclobutylamine, di-n-butylamine,piperidine, morpholine and pyrrolidine. Y

The present process is normally carried out at a temperature of fromabout 100 C. to about 300 C. and preferably between 150 C. and 250 C.The rate at'which the formation of the symmetrical 4-(dialkylamino)phenols take place has been found to vary with the temperature employed;longer periods being employed at the lower temperature. The reaction canbe carried out at atmospheric pressure depending upon the boiling pointof the amine reactant and, preferably, the reaction should be carriedout at above atmospheric pressure. For ease in operation, the reactionis preferably carried out in a closed vessel employing the autogenouspressure of the reactants. When operating within the preferredtemperature limits, reaction times of fromabout 0.5 to about 24 hoursare usually suflicient for practical completion.

In an additional procedure, product yield increases of from about 3 toabout 10 percent above those obtained by the general procedure directlyabove canbe obtained by carrying out the present process in the presenceof'an inert co-solvent which is immiscible with the amine-water phase.Representative co-solvents usable in the present process include, forexample, toluene, benzene, xylene, hexane, heptane and methylcyclohexane. r

In an alternative procedure, substantial product yield increases of fromabout 5 to about 20 percent over the general procedure set forth abovecan be obtained by pumping the 4-bromophenol reactant, dissolved in asuitable solvent, into the hot amine solution over a of from about 0.5to about 6 hours.

At the completion of the reaction, the reaction mixture can be purifiedby conventional procedures. One such period procedure is set forthhereinafter. The reaction mixture is extracted with a halohydrocarbonsolvent such as, for example, methylene chloride, ethylene dichloride,chloroform or carbon tetrachloride. The solvent phase is furtherextracted with an'aqueous acid such as, for example, aqueoushydrochloric acid, aqueous sulfuric acid, aqueous formic acid or aqueousacetic acid. The aqueousacidic phase is neutralized with a base such as,for example, aqueous ammonia, aqueous sodium hydroxide or aqueouspotassium hydroxide and further extracted with one of theabove-mentioned halohydrocarbon solvents. The solvent phase containingthe crude product is dried, filtered and the solvent removed byconventional techniques such as evaporation under reduced pressure.

An alternate work-up procedure for product recovery comprises extractingthe reaction mixture with a solvent such as ethylene dichloride followedby distillation of the solvent phase and finally distilling the productin a fractionating column under a partial vacuum. r

DESCRIPTION OF SOME PREFERRED EMBODIMENTS In order that the presentinvention may be more fully understood, the following examples are givenprimarily by way' of illustration and should not be construed aslimitations upon the overall scope of the present invention.

Example I i To a mixture of 225 grams (5 moles) of dimethylaminedissolved in 150 milliliters of water was added 86.5 grams (0.5 mole) of4-bromophenol. The mixture was placed in a pressure reaction apparatusand heated for 5 hours at about 200 C. The pressure was about 540 poundsper square inch. Thereafter the reaction mixture was cooled, in thereactor, and acidified with concentrated hydrochloric acid and extractedwith three 200 milliliter portions of methylene chloride. The solventphase was neutralized with aqueous ammonia and again extracted withmethylene chloride. The residual methylene chloride was removed byevaporation under reduced pressure leaving about 8 grams (-10 percent oftheoretical) of a crude 4-dimethylaminophenol product. The product wasrecrystallized from petroleum ether and melted at 75 -77 C. Its,structure was confirmed by nuclear magnetic resonance spectroscopy(N.M.R.).

Example II To amixture of225 grams (5 moles) of dimethylamine dissolvedin 150 milliliters of water was added 93.5 grams (0.5.mole) of4-bromo-3-methylphenol. The mixture was placed in a pressure reactionapparatus and heated for 5 hours at 200205 C. The pressure was about 540pounds per square inch. Thereafter the reaction mixture was cooled inthe reactor and acidified with concentrated bydrochloric acid. Themixture was extracted with three 200 milliliter portions of methylenechloride and neutralized with aqueous ammonia followed by an extractionwith three 200 milliliter portions of methylene chloride. Evaporation ofthe retained solvent gave -41 grams (51 percent of theoretical) of4-dimethylamino-3-methylphenol asthe product. 'The product was confirmedby nuclear magnetic resonance spectroscopy (N.M.R.).

Example III A'homogeneous solution was prepared containing grams (0.5mole) of 4-bromo-3,S-dimethylphenol, 225 grams (5 moles) ofdimetyhlamine and milliliters of water. The solution was placed in apressure reaction apparatus and heated for 2.5 hours at a temperature of210. to 215 C. The reaction mixture was cooled in the closed vessel andthereafter removed and extracted with 300 milliliters of methylenechloride. The solvent phase was thereafter extracted with 500 milliltersof aqueous hydrochloric acid (0.1 N), and neutralized with aqueousammonia. The oil which precipitated was extracted wtih 300 millilitersof methylene chloride, dried over calcium sulfate, filtered, and theresidual methylenechloride removed by evaporation under reducedpressure. The 4-dimethylamino-3,5-dimcthylphenol product wasrecoveredfrom the residue by distilling at 148-150 C. at millimeters ofmercury in a yield of-49.8 grams (61 percent of theore-' tical) andmelted at 84-85 C 1 Example I V A mixture was prepared containing 50grams (0.25 mole) of 4-bromo-3,5-dimethylphenol, 200 grams (2.3 .5moles) of piperidine and 200 milliliters of water. This mixture wasplaced in a pressure reaction vessel and heated at a temperature between200-225 C. for about 15 hours. To the reaction mixture was added gramsof sodium hydroxide and thereafter the water was removed by evaporationon a rotary evaporator. The residue was dissolved in a water-methylenechloride mixture and the water layer which formed was separated. Themethylene chloride layer was washed with water followed by acidificationwith sulfuric acid. The acid layer was extracted with methylenechloride, filtered, neutralized with aqueous ammonia and filtered again.The 4-piperidino-3,5-dimethylphenol product was purified by sublimationand recovered in a yield of 22 grams (54 percent of theoretical). Thestructure was confirmed by nuclear magnetic resonance spectroscopy.

Example V A mixture was prepared containing 50 grams (0.25 mole) of4-bromo-3,S-dimethylphenol, 190 grams (2.7 moles) of pyrrolidine and 190milliliters of water. This mixture was placed in a pressure reactionvessel and heated at a temperature between 210-225 C. for about 2 /2hours. The reaction mixture was treated in a manner substantially thesame as set forth above in Example IV. The4-pyrrolidino-3,S-dimethylphenol product was recovered in a yield of 21grams (51 percent of theoretical).

Following the general procedure as set forth hereinabove, the following4-(dialkylamino)phenols are prepared:

4-(dimethylamino)-2-methylphenol, having a molecular weight of 151.09,prepared by the reaction of 4-bromo-2- methylphenol and dimethylamine.

4-(dimethylamino) 2,3,5 trimethylphenol, having a molecular weight of179.11, prepared by the reaction of 4- bromo-Z,3,5-trimethylphenol anddimethylamine.

4-dimethylamino-2,3,5,6-tetramethoxyphenyl, having a molecular weight of257.12, prepared by the reaction of 4-bromo-2,3,5,6-tetramethoxyphenoland dimethylamine.

4-morpholino-3-butoxyphenol, having a molecular weight of 251.14,prepared by the reaction of 4-bromo-3- butoxyphenol and morpholine.

4-dibuty1amino-3,S-diethylphenol, having a molecular weight of 277.18,prepared by the reaction of 4-bromo- 3,5-diethylphenol and dibutylamine.

Example VI A solution, consisting of 202 grams (1.0 mole) ofrecrystalized 4-bromo-3,5-dimethylphenol in 150 milliliters of 40percent aqueous dimethylamine, was pumped over a 3 hour period into asteel reaction vessel containing 1000 grams of 40 percent aqueousdimethylamine heated to a temperature of 190 C. at an autogenouspressure of 580 pounds per square inch. After a one hour post additionheating period to maintain the temperature, the reaction vessel wascooled and the unreacted dimethylamine removed by distillation. Theresidue remaining was extracted three times with 100 milliliter portionsof methylene chloride and the extracts dried. The solvent was thereafterremoved and the residue subjected to fractional distillation. The4-dimethylamino 3,5 dimethylphenol product distilled at 152-l64 C. at 27milliliters of mercury and was recovered in a yield of 120.5 grams (73percent of theoretical).

5 By following the above examples and employing the appropriate amineand phenol reactants, the 4-(dialkylamino)-phenols of this invention,which are not shown being prepared ,by example, are prepared.

Preparation of Starting Materials The 4-bromophenols employed asstarting materials are prepared'by a procedure similar to the one taughtin U.S. Pat. 2,719,851 wherein, an appropriate phenol in glacial aceticacid is treated with a solution of'bromine in glacial aceticacid at atemperature of from 1525C. The desired 4 bromopheno1 product is obtainedby treating the product mixture with ice and 50 percent sodium hydroxidefollowed by recrystallization from a solvent such as n-pentane.

What is claimed is:

1. A process for preparing symmetrical 4-(dialkylamino) phenolscorresponding to the formula wherein R represents loweralkyl of 1 to 4carbon atoms or both R groups taken together with the nitrogen atomrepresent piperidino, morpholino or pyrrolidino; X represents loweralkylof 1 to 4 carbon atoms or loweralkoxy of 1 to 4 carbon atoms and nrepresents an integer of 0 to 3 with the proviso that when X is tertiarybutyl or tertiary 'butoxy, that only one such moiety can be in a ringposition alpha to the amino nitrogen, which consists essentially ofreacting in an inert polar solvent, a 4-bromophenol of the formulawherein X and n are as set forth hereinbefore, with a compound of theformula wherein R is as set forth hereinbefore, at a pressure aboveatmospheric pressure and at a temperature of from about C. to about 300C.

2. The process as defined in Claim 1 wherein the inert polar solvent iswater and the temperature is from about to about 250 C.

3. The process as defined in Claim 2 wherein an inert co-solvent is alsoemployed.

4. The process as defined in Claim 2 wherein the process is carried outin a closed reaction vessel employing the autogenous pressure of thereactants.

5. The process as defined in Claim 1 wherein the 4- bromophenol reactantis 4-bromo-3,S-dimethylphenol and the amine reactant is dimethylamine.

6. The process as defined in Claim 5 wherein the inert polar solvent iswater and the temperature is from about 150 to about 250 C.

7. The process as defined in Claim 5 wherein the phenol reactant isadded to a previously heated amine reactant.

8. The process as defined in Claim 6 wherein an inert co-solvent is alsoemployed.

9. The process as defined in Claim 1 wherein the 4- bromophenol is4-bromo-3-methylphenol and the amine reactant is dimethylamine.

10. The process as defined in Claim 1 wherein the molar ratios of theamine reactant to the phenol reactant is from about 1 to 1 to about 10to 1 and the weight ratio of reactant is pyrrolidine and; the phenolreactant is 4bromo 10 3,5-dimethylphenol.

h Ref er ence s Citd h D TPA E ATEN t 2,618,657 all/1952; Vaughn etal-"- f"..- 260-570.5

5 NORMA SL- -MILESTONEQ P rimary Examiner f S. D. WINTERS, AssistantExaminer U.s. 'C1. X.R.

1. A PROCESS FOR PREPARING SYMMETRICAL 4-(DIALKYLAMINO)PHENOLSCORRESPONDING TO THE FORMULA